Assembly and disassembly of the stromal architecture in the tumor microenvironmen

肿瘤微环境中基质结构的组装和拆卸

• 批准号: 7945297
• 负责人: Frank C. Marini
• 金额: $ 50万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7945297
• 关键词: Architecture; Blood Vessels; Bone Marrow; CD44 Antigens; CD44 gene; Cancer Center; Cell surface; Cells; Color; Complex; Development; Distant; Elements; Environment; Fatty acid glycerol esters; Fibroblasts; Generations; Genes; Growth Factor; Heterogeneity; Hyaluronic Acid; Immune; Indium; Individual; Label; LacZ Genes; Ligands; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mesenchymal Stem Cells; Mesenchyme; Methods; Modeling; Mus; Myelogenous; Neoplasm Transplantation; Nutrient; Nutritional; Play; Population; Proteins; Recruitment Activity; Relative (related person); Reporter Genes; Role; Source; Stromal Cells; Stromal Neoplasm; Surveys; Testing; Therapeutic Intervention; Tissues; Transgenic Animals; Transplantation; Transplanted tissue; Variant; bone; cytokine; in vivo; meetings; migration; neoplastic; neuronal cell body; novel; osteopontin; paracrine; progenitor; promoter; public health relevance; receptor; response; stem cell population; suicide gene; tumor; tumor growth; wasting

DESCRIPTION (provided by applicant): In response to: 14-CA-102 Understanding the Heterogeneity of Cancer and its Environment. Assembly and disassembly of stromal architecture in the tumor microenvironment. Frank Marini- UTM.D. Anderson Cancer Center To meet the requirements for rapid tumor growth, a complex array of non-neoplastic vascular, fibroblastic, and immune cells are recruited into the tumor microenvironment to provide structural, vascular, and paracrine support. Understanding the origin and composition of these stromal elements will help identify potential targets for therapeutic intervention that deprive the tumor of nutritional and/or structural requirement. Our proposed studies aim at understanding the role of various stromal elements in the tumor microenvironment and elucidate the contribution of MSC in generation of tumor-associated stroma. By using a two pronged approach of multicolor cellular transplant, and by utilizing a novel multi-reporter gene transgenic animal (the "rainbow" stroma mouse) generated by us to evaluate and understand the complex dynamic interactions of tumor and stromal components in vivo. This mouse possesses fluorescently labeled cells and multiple colored bone marrow resident precursor populations: (LacZ-labeled endothelial progenitor (Tie2 promoter), GFP-labeled myeloid progenitors (cFMS-promoter), YFP-bone marrow fibroblasts/mesenchyme (FSP1-promoter) known to participate in tumor stroma formation. Transplanted tumors developing in the rainbow mouse recruit labeled cell populations, as tumor structural elements that originate from gene marked populations will be surveyed, identified, and quantitated. Objective/hypothesis: We hypothesize that stromal precursor elements originate from bone marrowand fat-derived progenitor populations and are recruited to form tumor stroma and this recruitment is mediated through CD44. PUBLIC HEALTH RELEVANCE: Tumor growth is reliant on other cells of the body to produce supportive stroma, without stroma a tumor will stop growing. We have uncovered that a normal stem cell population, called mesenchymal stem cells (MSC) play a key role in tumor stroma formation, and their recruitment into the tumor. This project relates to the better understanding of why MSC are recruited to tumors and provides a rationale for potentially targeting stroma as a method to control or eliminate tumor growth.

描述（由申请人提供）：响应：14-CA-102了解癌症及其环境的异质性。 肿瘤微环境中基质结构的组装和拆卸。弗兰克·马里尼（Frank Mariniu utm.d.）安德森癌症中心 为了满足快速肿瘤生长的需求，将一系列非塑性血管，成纤维细胞和免疫细胞的复杂阵列募集到肿瘤微环境中，以提供结构性，血管和旁分泌支持。了解这些基质元素的起源和组成将有助于确定剥夺肿瘤营养和/或结构需求的治疗干预措施的潜在靶标。 我们提出的研究旨在了解各种基质元素在肿瘤微环境中的作用，并阐明MSC在肿瘤相关基质的产生中的贡献。通过使用一种多色细胞移植的两种叉式方法，并利用我们生成的一种新型多发性基因转基因动物（“彩虹”基质小鼠）来评估和了解体内肿瘤和基质成分的复杂动态相互作用。 This mouse possesses fluorescently labeled cells and multiple colored bone marrow resident precursor populations: (LacZ-labeled endothelial progenitor (Tie2 promoter), GFP-labeled myeloid progenitors (cFMS-promoter), YFP-bone marrow fibroblasts/mesenchyme (FSP1-promoter) known to participate in tumor stroma formation. Transplanted将在彩虹小鼠募集标记的细胞群体中发育的肿瘤，因为将调查，鉴定和定量源自基因标记种群的肿瘤结构元素。 客观/假设：我们假设基质前体元素起源于骨髓和脂肪衍生的祖细胞种群，并被募集以形成肿瘤基质，并且该募集是通过CD44介导的。 公共卫生相关性：肿瘤生长依赖于人体的其他细胞产生辅助基质，而没有基质的肿瘤将停止生长。我们发现，称为间充质干细胞（MSC）的正常干细胞群在肿瘤基质形成中起关键作用，并将其募集到肿瘤中。该项目涉及更好地理解为什么将MSC招募到肿瘤中，并为将基质作为控制或消除肿瘤生长的方法提供了理由。